Preferentially substituted calcium channel blockers

ABSTRACT

Certain piperazine substituted compounds are described which are useful in altering calcium channel activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 10/060,900filed 29 Jan. 2002 now U.S. Pat. No. 6,617,322 which is a continuationof U.S. Ser. No. 09/476,927 filed 30 Dec. 1999, now U.S. Pat. No.6,387,897; which is a continuation-in-part of U.S. Ser. No. 09/401,699,filed 23 Sep. 1999, now U.S. Pat. No. 6,294,533; which is acontinuation-in-part of U.S. Ser. No. 09/107,037 filed 30 Jun. 1998, nowU.S. Pat. No. 6,011,035. The contents of these applications areincorporated herein by reference.

TECHNICAL FIELD

The invention relates to compounds useful in treating conditionsassociated with abnormal calcium channel function. More specifically,the invention concerns compounds containing substituted or unsubstitutedderivatives of 6-membered heterocyclic moieties that are useful intreatment of conditions such as stroke and pain.

BACKGROUND ART

PCT publication WO 01/45709 published 28 Jun. 2001 discloses calciumchannel blockers where a piperidine or piperazine ring links abenzhydril moiety to an additional aromatic moiety or benzhydril. Thispublication, which is based on parent application Ser. No. 09/476,927,discussed above, is incorporated herein by reference. As explained inthese applications, native calcium channels have been classified bytheir electrophysiological and pharmacological properties as T, L, N, Pand Q types. T-type (or low voltage-activated) channels describe a broadclass of molecules that transiently activate at negative potentials andare highly sensitive to changes in resting potential. The L, N, P andQ-type channels activate at more positive potentials (high voltageactivated) and display diverse kinetics and voltage-dependentproperties. There is some overlap in biophysical properties of the highvoltage-activated channels, consequently pharmacological profiles areuseful to further distinguish them. Whether the Q- and P-type channelsare distinct molecular entities is controversial. Several types ofcalcium conductances do not fall neatly into any of the above categoriesand there is variability of properties even within a category suggestingthat additional calcium channels subtypes remain to be classified.

Biochemical analyses show that neuronal high voltage activated calciumchannels are heterooligomeric complexes consisting of three distinctsubunits (α₁, α₂δ and β). The α₁ subunit is the major pore-formingsubunit and contains the voltage sensor and binding sites for calciumchannel antagonists. The mainly extracellular α₂ is disulfide-linked tothe transmembrane δ subunit and both are derived from the same gene andare proteolytically cleaved in vivo. The β subunit is a nonglycosylated,hydrophilic protein with a high affinity of binding to a cytoplasmicregion of the α₁ subunit. A fourth subunit, γ, is unique to L-typecalcium channels expressed in skeletal muscle T-tubules.

Recently, each of these α₁ subtypes has been cloned and expressed, thuspermitting more extensive pharmacological studies. These channels havebeen designated α_(1A)–α_(1I) and α_(1S) and correlated with thesubtypes set forth above. α_(1A) channels are of the P/Q type; α_(1B)represents N; α_(1C), α′_(1D), α_(1F) and α_(1S) represent L; α_(1E)represents a novel type of calcium conductance, and α_(1G)–α_(1I)represent members of the T-type family.

Further details concerning the function of N-type channels, which aremainly localized to neurons, have been disclosed, for example, in U.S.Pat. No. 5,623,051, the disclosure of which is incorporated herein byreference. As described, N-type channels possess a site for bindingsyntaxin, a protein anchored in the presynaptic membrane. Blocking thisinteraction also blocks the presynaptic response to calcium influx.Thus, compounds that block the interaction between syntaxin and thisbinding site would be useful in neural protection and analgesia. Suchcompounds have the added advantage of enhanced specificity forpresynaptic calcium channel effects.

U.S. Pat. No. 5,646,149 describes calcium channel antagonists of theformula A-Y-B wherein B contains a piperazine or piperidine ringdirectly linked to Y. An essential component of these molecules isrepresented by A, which must be an antioxidant; the piperazine orpiperidine itself is said to be important. The exemplified compoundscontain a benzhydril substituent, based on known calcium channelblockers (see below). In some cases, the antioxidant can be a phenylgroup containing methoxy and/or hydroxyl substituents. In most of theillustrative compounds, however, a benzhydril moiety is coupled to theheterocycle simply through a CH group or C═ group. In the few compoundswhere there is an alkylene chain between the CH to which the two phenylgroups are bound and the heterocycle, the antioxidant must be coupled tothe heterocycle through an unsubstituted alkylene and in most of thesecases the antioxidant is a bicyclic system. Where the antioxidant cansimply be a phenyl moiety coupled through an alkynylene, the linker fromthe heterocycle to the phenyl moieties contains no more than six atomsin the chain. U.S. Pat. No. 5,703,071 discloses compounds said to beuseful in treating ischemic diseases. A mandatory portion of themolecule is a tropolone residue; among the substituents permitted arepiperazine derivatives, including their benzhydril derivatives. U.S.Pat. No. 5,428,038 discloses compounds which are said to exert a neuralprotective and antiallergic effect. These compounds are coumarinderivatives which may include derivatives of piperazine and othersix-membered heterocycles. A permitted substituent on the heterocycle isdiphenylhydroxymethyl. Thus, approaches in the art for variousindications which may involve calcium channel blocking activity haveemployed compounds which incidentally contain piperidine or piperazinemoieties substituted with benzhydril but mandate additional substituentsto maintain functionality.

Certain compounds containing both benzhydril moieties and piperidine orpiperazine are known to be calcium channel antagonists and neurolepticdrugs. For example, Gould, R. J., et al., Proc Natl Acad Sci USA (1983)80:5122–5125 describes antischizophrenic neuroleptic drugs such aslidoflazine, fluspirilene, pimozide, clopimozide, and penfluridol. Ithas also been shown that fluspirilene binds to sites on L-type calciumchannels (King, V. K. et al. J Biol Chem (1989) 264:5633–5641) as wellas blocking N-type calcium current (Grantham, C. J. et al. Brit JPharmacol (1944) 111:483–488). In addition, Lomerizine, as developed byKanebo KK, is a known calcium channel blocker; Lomerizine is, however,not specific for N-type channels. A review of publications concerningLomerizine is found in Dooley, D., Current Opinion in CPNSInvestigational Drugs (1999) 1:116–125.

In addition, benzhydril derivatives of piperidine and piperazine aredescribed in PCT publication WO 00/01375 published 13 Jan. 2000 andincorporated herein by reference. This PCT publication corresponds toparent application Ser. No. 09/401,699 set forth above. Reference tothis type of compound as known in the prior art is also made in WO00/18402 published 6 Apr. 2000 and in Chiarini, A., et al., Bioorganicand Medicinal Chemistry, (1996) 4:1629–1635.

Various other piperidine or piperazine derivatives containing arylsubstituents linked through nonaromatic linkers are described as calciumchannel blockers in U.S. Pat. No. 5,292,726; WO 99/43658; Breitenbucher,J. G., et al., Tat Lett (1998) 39:1295–1298.

The present invention provides additional compounds which comprisebenzhydril coupled to an acetyl group in turn coupled to a piperazinering. The piperazine ring is, in turn, substituted by a variety ofsubstituents, none of them antioxidants. These compounds are effectivein blocking calcium ion channels.

DISCLOSURE OF THE INVENTION

The invention relates to compounds useful in treating conditions such asstroke, head trauma, migraine, chronic, neuropathic and acute pain,epilepsy, hypertension, cardiac arrhythmias, and other indicationsassociated with calcium metabolism, including synaptic calciumchannel-mediated functions. The compounds of the invention arebenzhydril derivatives of piperazine with substituents that enhance thecalcium channel blocking activity of the compounds.

Thus, in one aspect, the invention is directed to compounds of theformula

wherein each R¹–R³ is independently a non-interfering substituent;

wherein a combination of R² and R³ may form a bridge between phenylgroups which may be a bond, a CR₂ group, an NR group, O, or S whereinthe S is optionally oxidized;

n¹ is 0–4 and n² and n³ are independently 0–5; and

wherein X is selected from the group consisting of:

(a) alkyl (1–12C) or alkenyl (2–12C) optionally including one or more N,O or S with the proviso that any N included in a ring is secondary or istertiary solely because of an alkyl substitution;

(b) aryl, provided that if aryl is phenyl or pyridyl, said aryl mustcontain at least one substituent and wherein if said aryl is phenyl andcontains only one substituent, said substituent must comprise an arylgroup or a trialkylsilyl group and wherein said phenyl is not2,3-dimethylphenyl or fused to an aliphatic ring;

(c) CRH-aryl wherein R is H, alkyl, or a heteroaromatic ring, whereinwhen R is H, aryl is optionally substituted 4-pyridyl, or is substitutedphenyl other than phenyl fused to an aliphatic ring, or is substitutednaphthyl or is substituted 5-membered aryl; and

(d) alkylene-aryl wherein said alkylene contains at least 2 C, andfurther optionally contains one heteroatom and/or is substituted by ═Oand/or OH provided that if said alkylene is CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂Oor CH₂CH₂CH₂O, and said aryl is phenyl, said phenyl must be substituted;and if said alkylene is CH₂CH₂CH₂O substituted by OH, said aryl is otherthan substituted quinolyl or monosubstituted phenyl.

Non-interfering substituents are, generally, optionally substitutedalkyl (1–12C), alkenyl (2–12C), alkynyl (2–12C), aryl (6–12C) orarylalkyl, arylalkenyl or arylalkynyl (each 7–16C) wherein in each ofthe foregoing 1–4C may be replaced by a heteroatom (Si, N, O and/or S)and wherein said optional substituents may include ═O. When alkyl,alkenyl, or alkynyl comprises at least one cyclic moiety, the number ofC contained may be as many as 15, again wherein one or more C may bereplaced by a heteroatom. Thus, for example, R¹–R³ may independently bein the form of an acyl, amide, or ester linkage with the ring carbon towhich it is bound.

“Non-interfering substituents” also include halo, CF₃, OCF₃, CN, NO₂,NR₂, OR, SR, COOR, or CONR₂, wherein R is H or optionally substitutedalkyl, alkenyl, alkynyl, aryl, or arylalkyl as described above. Twosubstituents at adjacent positions on the same ring may form a 3–7membered saturated or unsaturated ring fused to said substituted ring,said fused ring optionally itself substituted and optionally containsone or more heteroatoms (N, S, O). R¹ may be keto if n¹ is 1 or 2.

The invention is also directed to methods to modulate calcium channelactivity, preferably N-type and/or T-type channel activity, using thecompounds of formula (1) and thus to treat certain undesirablephysiological conditions; these conditions are associated with abnormalcalcium channel activity. In another aspect, the invention is directedto pharmaceutical compositions containing these compounds, and to theuse of these compounds for the preparation of medicaments for thetreatment of conditions requiring modulation of calcium channelactivity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-1 to 1-7 show illustrative compounds of the invention.

FIG. 2 is a graph showing the selectivity of compound P24 of theinvention for N-type, P/Q-type and L-type channels.

FIG. 3 is a graph showing the selectivity of compound P28 of theinvention for N-type, P/Q-type and L-type channels.

MODES OF CARRYING OUT THE INVENTION

The compounds of formula (1) useful in the methods of the inventionexert their desirable effects through their ability to modulate theactivity of N-type and/or T-type calcium channels. This makes themuseful for treatment of certain conditions. Among such conditions whereantagonist activity is desired are stroke, epilepsy, head trauma,migraine, inflammatory bowel disease and chronic, neuropathic and acutepain. Calcium flux is also implicated in other neurological disorderssuch as schizophrenia, anxiety, depression, other psychoses, and neuraldegenerative disorders. Other treatable conditions includecardiovascular conditions such as hypertension and cardiac arrhythmias.In addition, T-type calcium channels have been implicated in certaintypes of cancer, diabetes, infertility and sexual dysfunction.

While the compounds of formula (1) generally have this activity,availability of this class of calcium channel modulators permits anuanced selection of compounds for particular disorders. Theavailability of this class of compounds provides not only a genus ofgeneral utility in indications that are affected by excessive calciumchannel activity, but also provides a large number of compounds whichcan be mined and manipulated for specific interaction with particularforms of calcium channels. The availability of recombinantly producedcalcium channels of the α_(1A)–α_(1I) and α_(1S) types set forth above,facilitates this selection process. Dubel, S. J., et al., Proc Natl AcadSci USA (1992) 89:5058–5062; Fujita, Y., et al., Neuron (1993)10:585–598; Mikami, A., et al., Nature (1989) 340:230–233; Mori, Y., etal., Nature (1991) 350:398–402; Snutch, T. P., et al., Neuron (1991)7:45–57; Soong, T. W., et al., Science (1993) 260:1133–1136; Tomlinson,W. J., et al., Neuropharmacology (1993) 32:1117–1126; Williams, M. E.,et al., Neuron (1992) 8:71–84; Williams, M. E., et al., Science (1992)257:389–395; Perez-Reyes, et al., Nature (1998) 391:896–900; Cribbs, L.L., et al., Circulation Research (1998) 83:103–109; Lee, J. H., et al.,Journal of Neuroscience (1999) 19:1912–1921.

It is known that calcium channel activity is involved in a multiplicityof disorders, and particular types of channels are associated withparticular conditions. The association of N-type channels in conditionsassociated with neural transmission would indicate that compounds of theinvention which target N-type channels are most useful in theseconditions. Many of the members of the genus of compounds of formula (1)exhibit high affinity for N-type channels and/or T-type channels. Thus,as described below, they are screened for their ability to interact withN-type and T-type channels as an initial indication of desirablefunction. It is desirable that the compounds exhibit IC₅₀ values of <1μM. The IC₅₀ is the concentration which inhibits 50% of the calcium fluxat a particular applied potential.

There are two distinguishable types of calcium channel inhibition. Thefirst, designated “open channel blockage,” is conveniently demonstratedwhen displayed calcium channels are maintained at an artificiallynegative resting potential of about −100 mV (as distinguished from thetypical endogenous resting maintained potential of about −70 mV). Whenthe displayed channels are abruptly depolarized under these conditions,calcium ions are caused to flow through the channel and exhibit a peakcurrent flow which then decays. Open channel blocking inhibitorsdiminish the current exhibited at the peak flow and can also acceleratethe rate of current decay.

This type of inhibition is distinguished from a second type of block,referred to herein as “inactivation inhibition.” When maintained at lessnegative resting potentials, such as the physiologically importantpotential of −70 mV, a certain percentage of the channels may undergoconformational change, rendering them incapable of being activated—i.e.,opened—by the abrupt depolarization. Thus, the peak current due tocalcium ion flow will be diminished not because the open channel isblocked, but because some of the channels are unavailable for opening(inactivated). “Inactivation” type inhibitors increase the percentage ofreceptors that are in an inactivated state.

In order to be maximally useful in treatment, it is also helpful toassess the side reactions which might occur. Thus, in addition to beingable to modulate a particular calcium channel, it is desirable that thecompound has very low activity with respect to the HERG K⁺ channel whichis expressed in the heart. Compounds that block this channel with highpotency may cause reactions which are fatal. Thus, for a compound thatmodulates the calcium channel, it should also be shown that the HERG K⁺channel is not inhibited. Similarly, it would be undesirable for thecompound to inhibit cytochrome p450 since this enzyme is required fordrug detoxification. Finally, the compound will be evaluated for calciumion channel type specificity by comparing its activity among the varioustypes of calcium channels, and specificity for one particular channeltype is preferred. The compounds which progress through these testssuccessfully are then examined in animal models as actual drugcandidates.

The Invention Compounds

The substituents on the basic structures of formula (1) are describedabove. These include alkyl, alkenyl, alkynyl, etc., substituents.

As used herein, the term “alkyl,” “alkenyl” and “alkynyl” includestraight-chain, branched-chain and cyclic monovalent substituents,containing only C and H when they are unsubstituted or unless otherwisenoted. Examples include methyl, ethyl, isobutyl, cyclohexyl,cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. Typically, thealkyl, alkenyl and alkynyl substituents contain 1–10C (alkyl) or 2–12C(alkenyl or alkynyl). They may contain 1–6C (lower alkyl) or 2–6C (loweralkenyl or lower alkynyl), however, when the alkyl, alkenyl or alkynylgroups contain rings, they may contain as many as 18C, some of which mayoptionally be replaced by heteroatoms.

Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly defined butmay contain one or more O, S or N heteroatoms or combinations thereofwithin the backbone residue. In general, the terms alkyl, alkenyl andalkynyl include those wherein heteroatoms are contained when thusspecified.

As used herein, “acyl” encompasses the definitions of alkyl, alkenyl,alkynyl, each of which is coupled to an additional residue through acarbonyl group. Heteroacyl includes the related heteroforms.

“Aromatic” moiety or “aryl” moiety refers to a monocyclic or fusedbicyclic moiety such as phenyl or naphthyl which may also beheteroaromatic; “heteroaromatic” also refers to monocyclic or fusedbicyclic ring systems containing one or more heteroatoms selected fromO, S and N. The inclusion of a heteroatom permits inclusion of5-membered rings as well as 6-membered rings. Thus, typicalaromatic/heteroaromatic systems include pyridyl, pyrimidyl, indolyl,benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl,benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyland the like. Because tautomers are theoretically possible, phthalimidois also considered aromatic. Any monocyclic or fused ring bicyclicsystem which has the characteristics of aromaticity in terms of electrondistribution throughout the ring system is included in this definition.Typically, the ring systems contain 5–12 ring member atoms.

Similarly, “arylalkyl” and “heteroarylalkyl” refer to aromatic andheteroaromatic systems which are coupled to another residue through acarbon chain, including substituted or unsubstituted, saturated orunsaturated, carbon chains, typically of 1–8C, or the hetero formsthereof. These carbon chains may also include a carbonyl group, thusmaking them able to provide substituents as an acyl or heteroacylmoiety.

In general, any alkyl, alkenyl, alkynyl, acyl, or aryl group containedin a substituent may itself optionally be substituted by additionalsubstituents. The nature of these substituents is similar to thoserecited with regard to the primary substituents themselves. Thus, wherean embodiment of a substituent is alkyl, this alkyl may optionally besubstituted by the remaining substituents listed as substituents wherethis makes chemical sense, and where this does not undermine the sizelimit of alkyl per se; e.g., alkyl substituted by alkyl or by alkenylwould simply extend the upper limit of carbon atoms for theseembodiments. However, alkyl substituted by aryl, amino, alkoxy, and thelike would be included.

Non-interfering substituents on aryl groups in general include, but arenot limited to, optionally substituted alkyl, alkenyl, alkynyl, aryl,arylalkyl, and acyl, as well as halo, —CN, —CF₃, —NO, —NO₂, —OR, —NR₂,—SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, —RCO,—COOR, —NRSOR, —NRSO₂R, —SO₃R, —CONR₂, —SO₂NR₂, wherein each R isindependently H or alkyl (1–8C), and the like.

The compounds of the invention may have ionizable groups so as to becapable of preparation as pharmaceutically acceptable salts. These saltsmay be acid addition salts involving inorganic or organic acids or thesalts may, in the case of acidic forms of the compounds of the inventionbe prepared from inorganic or organic bases. Suitable pharmaceuticallyacceptable acids and bases are well-known in the art, i.e., acids suchas hydrochloric, sulphuric, citric, acetic, or tartaric acids and basessuch as potassium hydroxide, sodium hydroxide, ammonium hydroxide,caffeine, various amines, and the like. Methods for preparation of theappropriate salts are well-established in the art.

In addition, in some cases, the compounds of the invention contain oneor more chiral centers. The invention includes the isolatedstereoisomeric forms as well as mixtures of stereoisomers in varyingdegrees of chiral purity.

Synthesis of the Invention Compounds

The compounds of the invention modulate the activity of calciumchannels; in general, said modulation is the inhibition of the abilityof the channel to transport calcium. As described below, the effect of aparticular compound on calcium channel activity can readily beascertained in a routine assay whereby the conditions are arranged sothat the channel is activated, and the effect of the compound on thisactivation (either positive or negative) is assessed. Typical assays aredescribed hereinbelow.

The compounds of the invention may have ionizable groups so as to becapable of preparation as pharmaceutically acceptable salts. These saltsmay be acid addition salts involving inorganic or organic acids or thesalts may, in the case of acidic forms of the compounds of the inventionbe prepared from inorganic or organic bases. Suitable pharmaceuticallyacceptable acids and bases are well-known in the art, such ashydrochloric, sulphuric, citric, acidic, or tartaric acids and potassiumhydroxide, sodium hydroxide, ammonium hydroxide, caffeine, variousamines, and the like. Methods for preparation of the appropriate saltsare well-established in the art.

The compounds of the invention may be synthesized using conventionalmethods. Illustrative of such methods are Schemes 1 to 3.

Reaction Scheme 1 was used to prepare compounds P6–P8, P25, P30–P32,P36–P42 of the invention.

Reaction Scheme 2 was used to prepare compounds P9 and P10 of theinvention.

Reaction Scheme 3 was used to prepare compounds P1–P5, P12–P24, P27–P29,P33–P35 of the invention.

Preferred Embodiments

The compounds of formula (1) are defined as shown in terms of theembodiments of their various substituents.

Particularly preferred embodiments of Formula (1) are those wherein onlyzero, one or two of the depicted rings are substituted and wherein thenumber of substituents on a single ring is three or less. Particularlypreferred substituents for the phenyl rings shown include halo,especially fluoro or chloro; CF₃; optionally substituted, optionallyheteroatom-containing alkyl, alkenyl, aryl, alkyl aryl, alkenyl aryl,phenoxy, and the like. Where the substituents on these moieties containalkyl or aryl groups, these also may optionally be substituted. Alsopreferred are bridging substituents containing heteroatoms.

Particularly preferred substituents for the piperazine ring include ═O,COOR, especially COOH and COOEt, alkyl, and alkenyl, (as defined aboveand optionally containing heteroatoms and all optionally substituted)and halo.

Preferred embodiments of X include unsubstituted alkyl or alkenyl,including embodiments wherein one or two carbons are replaced by N, S orO. Also preferred are embodiments wherein X is arylalkyl, especiallywherein the aryl moiety is phenyl and wherein the alkyl moiety containsat least one heteroatom and/or is substituted by at least one ═O. Alsopreferred are embodiments wherein X is alkyl and is in a cyclic form,and thus may contain up to 15C, wherein one or more of said C mayoptionally be replaced by a heteroatom. Also preferred are embodimentswherein X comprises a heteroaryl moiety, such as pyridyl, pyrimidyl,benzimidazole, benzothiazole and the like. Also preferred areembodiments wherein X is arylalkyl wherein the alkyl group issubstituted by an aromatic or other cyclic moiety; especially preferredare those embodiments wherein the alkyl portion is methylene substitutedby a cyclic moiety. Also preferred are embodiments wherein X isarylalkyl, the aryl portion is phenyl and is multiply substituted or issubstituted by a substituent that comprises an additional aryl moiety.

Libraries and Screening

The compounds of the invention can be synthesized individually usingmethods known in the art per se, or as members of a combinatoriallibrary.

Synthesis of combinatorial libraries is now commonplace in the art.Suitable descriptions of such syntheses are found, for example, inWentworth, Jr., P., et al., Current Opinion in Biol. (1993) 9:109–115;Salemme, F. R., et al., Structure (1997) 5:319–324. The librariescontain compounds with various substituents and various degrees ofunsaturation, as well as different chain lengths. The libraries, whichcontain, as few as 10, but typically several hundred members to severalthousand members, may then be screened for compounds which areparticularly effective against a specific subtype of calcium channel,i.e., the N-type channel. In addition, using standard screeningprotocols, the libraries may be screened for compounds which blockadditional channels or receptors such as sodium channels, potassiumchannels and the like.

Methods of performing these screening functions are well known in theart. These methods can also be used for individually ascertaining theability of a compound to agonize or antagonize the channel. Typically,the channel to be targeted is expressed at the surface of a recombinanthost cell such as human embryonic kidney cells. The ability of themembers of the library to bind the channel to be tested is measured, forexample, by the ability of the compound in the library to displace alabeled binding ligand such as the ligand normally associated with thechannel or an antibody to the channel. More typically, ability toantagonize the channel is measured in the presence of calcium ion andthe ability of the compound to interfere with the signal generated ismeasured using standard techniques. In more detail, one method involvesthe binding of radiolabeled agents that interact with the calciumchannel and subsequent analysis of equilibrium binding measurementsincluding, but not limited to, on rates, off rates, K_(d) values andcompetitive binding by other molecules.

Another method involves the screening for the effects of compounds byelectrophysiological assay whereby individual cells are impaled with amicroelectrode and currents through the calcium channel are recordedbefore and after application of the compound of interest.

Another method, high-throughput spectrophotometric assay, utilizesloading of the cell lines with a fluorescent dye sensitive tointracellular calcium concentration and subsequent examination of theeffects of compounds on the ability of depolarization by potassiumchloride or other means to alter intracellular calcium levels.

As described above, a more definitive assay can be used to distinguishinhibitors of calcium flow which operate as open channel blockers, asopposed to those that operate by promoting inactivation of the channel.The methods to distinguish these types of inhibition are moreparticularly described in the examples below. In general, open-channelblockers are assessed by measuring the level of peak current whendepolarization is imposed on a background resting potential of about−100 mV in the presence and absence of the candidate compound.Successful open-channel blockers will reduce the peak current observedand may accelerate the decay of this current. Compounds that areinactivated channel blockers are generally determined by their abilityto shift the voltage dependence of inactivation towards more negativepotentials. This is also reflected in their ability to reduce peakcurrents at more depolarized holding potentials (e.g., −70 mV) and athigher frequencies of stimulation, e.g., 0.2 Hz vs. 0.03 Hz.

Utility and Administration

For use as treatment of human and animal subjects, the compounds of theinvention can be formulated as pharmaceutical or veterinarycompositions. Depending on the subject to be treated, the mode ofadministration, and the type of treatment desired—e.g., prevention,prophylaxis, therapy; the compounds are formulated in ways consonantwith these parameters. A summary of such techniques is found inRemington's Pharmaceutical Sciences, latest edition, Mack PublishingCo., Easton, Pa., incorporated herein by reference.

In general, for use in treatment, the compounds of formula (1) may beused alone, as mixtures of two or more compounds of formula (1) or incombination with other pharmaceuticals. Depending on the mode ofadministration, the compounds will be formulated into suitablecompositions to permit facile delivery.

Formulations may be prepared in a manner suitable for systemicadministration or topical or local administration. Systemic formulationsinclude those designed for injection (e.g., intramuscular, intravenousor subcutaneous injection) or may be prepared for transdermal,transmucosal, or oral administration. The formulation will generallyinclude a diluent as well as, in some cases, adjuvants, buffers,preservatives and the like. The compounds can be administered also inliposomal compositions or as microemulsions.

For injection, formulations can be prepared in conventional forms asliquid solutions or suspensions or as solid forms suitable for solutionor suspension in liquid prior to injection or as emulsions. Suitableexcipients include, for example, water, saline, dextrose, glycerol andthe like. Such compositions may also contain amounts of nontoxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents and the like, such as, for example, sodium acetate, sorbitanmonolaurate, and so forth.

Various sustained release systems for drugs have also been devised. See,for example, U.S. Pat. No. 5,624,677.

Systemic administration may also include relatively noninvasive methodssuch as the use of suppositories, transdermal patches, transmucosaldelivery and intranasal administration. Oral administration is alsosuitable for compounds of the invention. Suitable forms include syrups,capsules, tablets, as in understood in the art.

For administration to animal or human subjects, the dosage of thecompounds of the invention is typically 0.1–15 mg/kg, preferably 0.1–1mg/kg. However, dosage levels are highly dependent on the nature of thecondition, the condition of the patient, the judgment of thepractitioner, and the frequency and mode of administration.

The following examples are intended to illustrate but not to limit theinvention.

EXAMPLE 1 Synthesis of1-{4-[2-(2,4-difluoro-phenoxy)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one

A. Synthesis of 2-(2,4-difluoro-phenoxy)-ethanol

K₂CO₃ (1.07 g, 7.78 mmol) was added to a solution of 2,4-difluoro phenol(0.84 g, 6.48 mmol) in dry DMF (15 ml). 2-Bromoethanol (0.81 g, 6.48mmol) was added, and the mixture was heated overnight at 120° C. Themixture was cooled, taken up in EtOAc, extracted with water (20 ml),saturated NaCl (4×20 ml), dried over MgSO₄, and evaporated under reducedpressure. The product was purified by column chromatography on silica(Hexane:EtOAc 3:1) to give the desired product in 63% yield

B. Synthesis of 4-(2-bromo-ethoxy)-1,3-difluoro benzene

To a cool solution 2-(2,4-difluoro-phenoxy)-ethanol (0.48 g, 2.77 mmol.)in CH₂Cl₂ (15 ml), triphenyl phosphine (1.3 g, 5 mmol)) was added.Carbon tetrabromide (1.65 g, 5 mmol.) in CH₂Cl₂ (3 ml) was added to thesolution dropwise under N₂. The solution was stirred for 30 minutes.EtOAc was added, then the solvent was evaporated under reduced pressure.

The product was purified by column chromatography on silica(Hexane:EtOAc 1:1) to give the desired product in 83% yield.

C. Synthesis of 1-[2-(2,4-difluoro-phenoxy)-ethyl]-piperazine

A mixture of piperazine (8.7 g, 101.26 mmol) in butanone (70 ml),4-(2-bromo-ethoxy)-1,3-difluoro benzene (6.0 g, 25.31 mmol), anhydrousK₂CO₃ (3.5 g, 25.31 mmol) and KI (4.2 g, 25.31 mmol) was refluxed undernitrogen for 18 hours. The mixture was then cooled and filtered and thesolvent removed in vacuo. The residue was dissolved in CH₂Cl₂ (200 ml)and washed with water (50 ml). Drying and removal of the solventfollowed by chromatography (CH₂Cl₂:CH₃OH:NH₄OH 10:1) afforded desiredproduct in 73% yield.

To a solution of 1-[2-(2,4-difluoro-phenoxy)-ethyl]-piperazine (1.0 g,4.13 mmol) in dry CH₂Cl₂ (30 ml) was added 3,3-diphenylpropanoic acid(1.12 g, 4.95 mmol) under nitrogen. To the reaction was added EDC (1.0g, 5.36 mmol) and DMAP (cat) and the reaction mixture stirred undernitrogen at room temperature overnight. The reaction was thenconcentrated under reduced pressure. The residue dissolved in ethylacetate:water (10:1) (150 ml). The organic was washed with water (30 ml,2×) and 10% NaOH (30 ml) and dried over MgSO₄ and evaporated to dryness.The resulting residue was purified by column chromatography using ethylacetate to give desired product in 85% yield.

EXAMPLE 2 Synthesis ofN-(2,6-dimethyl-phenyl)-2-[4-(3,3-diphenyl-propionyl)-piperazin-1-yl]-acetamide

A. Synthesis of 4-(3,3-diphenyl-propionyl)-piperazine-1-carboxylic acidtert-butyl ester

To a solution of 3,3 diphenylpropionic acid (1.45 g, 6.44 mmol) in dryCH₂Cl₂ (70 ml) was added mono-boc piperizine (1.32 g, 7.08 mmol) undernitrogen. To the reaction was added EDC (2.71 g, 14.16 mmol) and DMAP(cat) and the reaction mixture stirred under nitrogen at roomtemperature overnight. The reaction was then concentrated under reducedpressure. The residue dissolved in ethyl acetate:water (10:1) (200 ml).The organic was washed with water (50 ml, 2×) and 10% NaOH (50 ml) anddried over MgSO₄ and evaporated to dryness. The resulting residue waspurified by column chromatography using hexane:ethyl acetate (1:1) togive desired product in 76% yield.

B. Synthesis of 3,3-diphenyl-1-piperazin-1-yl-propan-1-one

To a solution of 4-(3,3-diphenyl-propionyl)-piperazine-1-carboxylic acidtert-butyl ester (2.15 g, 5.45 mmol) in dry CH₂Cl₂ (60 ml) was added TFA(20 ml) and resulting mixture stirred at room temperature for 3 hrs.Solvent and excess TFA was then evaporated and the residue was dissolvedin CH₂Cl₂ (150 ml) and washed with sat. NaHCO₃ (2×) and dried overMgSO₄. Evaporation of solvent gave 1.65 g of pure product.

C. Synthesis of [4-(3,3-diphenyl-propionyl)-piperazin-1-yl]-acetic acidethyl ester

To a solution of 3,3-diphenyl-1-piperazin-1-yl-propan-1-one (2.0 g, 6.79mmol) and ethyl bromoacetate (0.94 ml, 8.49 mmol) in dry DMF (15 ml) wasadded K₂CO₃ (2.7 g, 19.53 mmol) and the mixture was heated to 70° C.overnight. Reaction mixture was cooled and water (32 ml) was added. Theproduct was extracted with ether, dried and evaporated. The residue waspurified by column chromatography using hexane:ethyl acetate (1:4) togive the desired product in 60% yield.

D. Synthesis of [4-(3,3-diphenyl-propionyl)-piperazin-1-yl]-acetic acid

A mixture of [4-(3,3-diphenyl-propionyl)-piperazin-1-yl]-acetic acidethyl ester (1.17 g, 3.07 mmol) and LiOH (645 mg, 15.35 mmol) in MeOH:H₂O (3:1, 40 ml) stirred at room temperature for 2 days. The solvent wasthen evaporated and residue dissolved in water. Upon acidified with 2NHCl to pH 3, product precipitated in aq. phase, filtered and washed fewtimes with water and dried to give the desired product in 78% yield.

To a solution of [4-(3,3-diphenyl-propionyl)-piperazin-1-yl]-acetic acid(0.8 g, 2.29 mmol) in dry CH₂Cl₂ (50 ml) was added 2,6-dimethyl aniline(0.28 ml, 2.29 mmol) under nitrogen. To the reaction was added EDC (0.87g, 4.58 mmol) and DMAP (cat) and the reaction mixture stirred undernitrogen at room temperature overnight. The reaction was thenconcentrated under reduced pressure. The residue dissolved in ethylacetate:water (10:1) (120 ml). The organic was washed with water (30ml,2×) and 10% NaOH (30 ml) and dried over MgSO₄ and evaporated to dryness.The resulting residue was purified by column chromatography usingCH₂Cl₂:MeOH (15:1) to give desired product in 72% yield.

EXAMPLE 3 Synthesis of1-[4-(1-methyl-piperidin-4-ylmethyl)piperazin-1-yl]-3,3-diphenyl-propan-1-one

To a solution of 1-(1-methyl-piperidin-4ylmethyl)-piperazine (0.25 g,1.26 mmol) in dry CH₂Cl₂ (25 ml) was added 3,3-diphenylpropanoic acid(0.26 g, 1.15 mmol) under nitrogen. To the reaction was added EDC (0.48g, 2.53 mmol) and DMAP (cat) and the reaction mixture stirred undernitrogen at room temperature overnight. The reaction was thenconcentrated under reduced pressure. The residue dissolved in ethylacetate:water (10:1) (100 ml). The organic was washed with water (25 ml,2×) and 10% NaOH (25 ml) and dried over MgSO₄ and evaporated to dryness.The resulting residue was purified by column chromatography usingCH₂Cl₂:MeOH (5:1) to give desired product in 69% yield.

EXAMPLE 4 N-type Calcium Channel Blocking Activities of VariousInvention Compounds

The methods of Example 1 were followed with slight modifications as willbe apparent from the description below.

A. Transformation of HEK Cells:

N-type calcium channel blocking activity was assayed in human embryonickidney cells, HEK 293, stably transfected with the rat brain N-typecalcium channel subunits (α_(1B)+α_(2δ)+β_(1b) cDNA subunits).Alternatively, N-type calcium channels (α_(1B)+α_(2δ)+β_(1b) cDNAsubunits), L-type channels (α_(1C)+α_(2δ)+β_(1b) cDNA subunits) andP/Q-type channels (α_(1A)+α_(2δ)+β_(1b) cDNA subunits) were transientlyexpressed in HEK 293 cells. Briefly, cells were cultured in Dulbecco'smodified eagle medium (DMEM) supplemented with 10% fetal bovine serum,200 U/ml penicillin and 0.2 mg/ml streptomycin at 37° C. with 5% CO₂. At85% confluency cells were split with 0.25% trypsin/1 mM EDTA and platedat 10% confluency on glass coverslips. At 12 hours the medium wasreplaced and the cells transiently transfected using a standard calciumphosphate protocol and the appropriate calcium channel cDNAs. Fresh DMEMwas supplied and the cells transferred to 28° C./5% CO₂. Cells wereincubated for 1 to 2 days to whole cell recording.

B. Measurement of Inhibition:

Whole cell patch clamp experiments were performed using an Axopatch 200Bamplifier (Axon Instruments, Burlingame, Calif.) linked to a personalcomputer equipped with pCLAMP software. The external and internalrecording solutions contained, respectively, 5 mM BaCl₂, 1 mM MgCl₂, 10mM HEPES, 40 mM TEACl, 10 mM glucose, 87.5 mM CsCl (pH 7.2) and 108 mMCsMS, 4 mM MgCl₂, 9 mM EGTA, 9 mM HEPES (pH 7.2). Currents weretypically elicited from a holding potential of −80 mV to +10 mV usingClampex software (Axon Instruments). Typically, currents were firstelicited with low frequency stimulation (0.03 Hz) and allowed tostabilize prior to application of the compounds. The compounds were thenapplied during the low frequency pulse trains for two to three minutesto assess tonic block, and subsequently the pulse frequency wasincreased to 0.2 Hz to assess frequency dependent block. Data wereanalyzed using Clampfit (Axon Instruments) and SigmaPlot 4.0 (JandelScientific).

Using the procedure set forth in this Example 4, various compounds ofthe invention were tested for their ability to block N-type calciumchannels. The results show IC₅₀ values in the range of 0.05–1 μM, asshown in Table 1.

TABLE 1 Block of α1B N-type Channels 0.067 Hz 0.2 Hz Compound IC50 (μM)IC50 (μM) P1 0.240 0.320 P2 0.387 0.292 P3 0.531 0.445 P6 0.520 0.360 P71.090 0.800 P9 >1 >1 P10 0.471 0.295 P11 0.660 0.480 P12 0.350 0.288 P130.554 0.413 P14 0.261 0.217 P15 0.534 0.321 P16 0.500 0.300 P17 0.3760.224 P18 0.110 0.076 P19 0.280 0.180 P20 0.430 0.240 P21 0.370 0.290P22 0.314 0.174 P23 0.650 0.410 P24 0.190 0.130 P25 0.421 0.275 P260.263 0.130 P27 0.715 0.371 P28 0.249 0.159 P29 0.361 0.298 P30 3.550.601 P31 0.597 0.398 P32 0.313 0.266 P33 0.240 0.180 P34 0.290 0.150P35 0.520 0.430 P36 0.450 0.350 P37 0.670 0.420 P38 0.183 0.135 P390.400 0.280 P40 0.364 0.308 P41 0.349 0.282

EXAMPLE 5 Assessment of Selective Calcium Channel Blocking Activity

Antagonist activity was measured using whole cell patch recordings onhuman embryonic kidney cells either stably or transiently expressing ratα_(1B)+α_(2b)+β_(1b) channels (N-type channels) with 5 mM barium as acharge carrier.

For transient expression, host cells, such as human embryonic kidneycells, HEK 293 (ATCC# CRL 1573) were grown in standard DMEM mediumsupplemented with 2 mM glutamine and 10% fetal bovine serum. HEK 293cells were transfected by a standard calcium-phosphate-DNAcoprecipitation method using the rat α_(1B)+β_(1b)+α₂δ N-type calciumchannel subunits in a vertebrate expression vector (for example, seeCurrent Protocols in Molecular Biology).

After an incubation period of from 24 to 72 hrs the culture medium wasremoved and replaced with external recording solution (see below). Wholecell patch clamp experiments were performed using an Axopatch 200Bamplifier (Axon Instruments, Burlingame, Calif.) linked to an IBMcompatible personal computer equipped with pCLAMP software. Borosilicateglass patch pipettes (Sutter Instrument Co., Novato, Calif.) werepolished (Microforge, Narishige, Japan) to a resistance of about 4 MΩwhen filled with cesium methanesulfonate internal solution (compositionin MM: 109 CsCH₃SO₄, 4 MgCl₂, 9 EGTA, 9 HEPES, pH 7.2). Cells werebathed in 5 mM Ba⁺⁺ (in mM: 5 BaCl₂, 1 MgCl₂, 10 HEPES, 40tetraethylammonium chloride, 10 glucose, 87.5 CsCl pH 7.2). Current datashown were elicited by a train of 100 ms test pulses at 0.066 Hz from−100 mV and/or −80 mV to various potentials (min. −20 mV, max. +30 mV).Drugs were perfused directly into the vicinity of the cells using amicroperfusion system.

Normalized dose-response curves were fit (Sigmaplot 4.0, SPSS Inc.,Chicago, Ill.) by the Hill equation to determine IC₅₀ values.Steady-state inactivation curves were plotted as the normalized testpulse amplitude following 5 s inactivating prepulses at +10 mVincrements. Inactivation curves were fit (Sigmaplot 4.0) with theBoltzman equation, I_(peak) (normalized)=1/(1+exp((V−V_(h))z/25.6)),where V and V_(h) are the conditioning and half inactivation potentials,respectively, and z is the slope factor.

Table 2 shows the results obtained with several compounds of theinvention which are selective for N-type channels. In addition, FIGS. 2and 3 show the specificity of compounds P24 and P28 of the inventionwhich selectively block N-type channels.

TABLE 2 Selectivity of Compounds for N-type Ca²⁺ Channels Tested at 0.1Hz, 5 mM Ba²⁺ N-type P/Q-type L-type IC₅₀ IC₅₀ IC₅₀ Compound (μM) (μM)(μM) P/Q:N ratio L:N ratio P24 0.257 2.449 ~30 9.5:1 117:1 P28 0.2146.446  20 9.5:1  93:1

EXAMPLE 6 Block of α_(1G) T-Type Channels

Standard patch-clamp techniques were employed to identify blockers ofT-type currents. Briefly, previously described HEK cell lines stablyexpressing human α_(1G) subunits were used for all the recordings(passage #: 4–20, 37° C., 5% CO₂). To obtain T-type currents, plasticdishes containing semi-confluent cells were positioned on the stage of aZEISS AXIOVERT S100 microscope after replacing the culture medium withexternal solution (see below). Whole-cell patches were obtained usingpipettes (borosilicate glass with filament, O.D.: 1.5 mm, I.D.: 0.86 mm,10 cm length), fabricated on a SUTTER P-97 puller with resistance valuesof ˜5 MΩ (see below for internal medium).

TABLE 3 External Solution 500 ml - pH 7.4, 265.5 mOsm Salt Final mMStock M Final ml CsCl 132 1  66 CaCl₂ 2 1   1 MgCl₂ 1 1 0.5 HEPES 10 0.5 10 glucose 10 — 0.9 grams

TABLE 4 Internal Solution 50 ml - pH 7.3 with CsOH, 270 mOsm Salt FinalmM Stock M Final ml Cs-Methanesulfonate 108 — 1.231 gr/50 ml MgCl₂ 2 1 0.1 HEPES 10 0.5    1 EGTA-Cs 11 0.25  2.2 ATP 2 0.2 0.025 (1aliquot/2.5 ml) T-type currents were reliably obtained by using twovoltage protocols: (1) “non-inactivating”, and (2) “inactivation”

In the non-inactivating protocol, the holding potential is set at −110mV and with a pre-pulse at −100 mV for 1 second prior to the test pulseat −40 mV for 50 ms. In the inactivation protocol, the pre-pulse is atapproximately −85 mV for 1 second, which inactivates about 15% of theT-type channels.

Test compounds were dissolved in external solution, 0.1–0.01% DMSO.After ˜10 min rest, they were applied by gravity close to the cell usinga WPI microfil tubing. The “non-inactivated” pre-pulse was used toexamine the resting block of a compound. The “inactivated” protocol wasemployed to study voltage-dependent block. However, the initial datashown below were mainly obtained using the non-inactivated protocolonly. IC₅₀ values are shown for various compounds of the invention inTable 5.

TABLE 5 Block of α_(1G) T-type Channels −100 mV −80 mV Compound IC50(μM) IC50 (μM) P19 0.154  P21 No effect P23 0.905  P30 No effect P330.0088 0.0022 P41 No effect

1. A compound of the formula:

or the salt or stereoisomeric forms thereof, wherein each R¹–R³ isindependently a non-interfering substituent; and wherein a combinationof R² and R³ may form a bridge between phenyl groups, which may be abond or a CR₂ group, an NR group, O, or S wherein the S is optionallyoxidized; n¹ is 0–4 and n² and n³ are independently 0–5; and wherein Xis selected from the group consisting of: (a) alkyl (1–12C) or alkenyl(2–12C) optionally including one or more N, O or S with the proviso thatany N included in a ring is secondary or is tertiary solely because ofan alkyl substitution; (b) aryl, provided that if aryl is phenyl orpyridyl, said aryl must contain at least one substituent and wherein ifsaid aryl is phenyl and contains only one substituent, said substituentmust comprise an aryl group or a trialkylsilyl group and wherein saidphenyl is not 2,3-dimethylphenyl or fused to an aliphatic ring; (c)—CRH-aryl wherein R is H, alkyl, or a heteroaromatic ring, wherein whenR is H, aryl is optionally substituted 4-pyridyl, or is substitutedphenyl other than phenyl fused to an aliphatic ring, or is substitutednaphthyl or is substituted 5-membered aryl; and (d) -alkylene-arylwherein said alkylene contains at least 2 C, and further optionallycontains one heteroatom and/or is substituted by ═O and/or OH providedthat if said alkylene is CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂O or CH₂CH₂CH₂O, andsaid aryl is phenyl, said phenyl must be substituted; and if saidalkylene is CH₂CH₂CH₂O substituted by OH, said aryl is other thansubstituted quinolyl or monosubstituted phenyl.
 2. The compound of claim1, wherein each R¹–R³ is independently halo, NO, NO₂, CN, SO₂H, SO₃H,optionally substituted alkyl (1–12C), alkenyl (2–12C), alkynyl (2–12C),aryl (6–12C) or arylalkyl, arylalkenyl or arylalkynyl (each 7–16C)wherein in each of the foregoing 1–4C may be replaced by a heteroatom(Si, N, O and/or S) and wherein said optional substituents may include═O and wherein when alkyl, alkenyl, or alkynyl comprises at least onecyclic moiety, the number of C contained may be up to and including 18,wherein one or more C may be replaced by a heteroatom, and wherein twosubstituents at adjacent positions on the same ring may form a 3–7membered saturated or unsaturated ring fused to said substituted ring,said fused ring is optionally itself substituted and optionally containsone or more heteroatoms (N, S, O), and wherein R¹ may be keto.
 3. Thecompound of claim 1, wherein X is alkyl (1–12C) or alkenyl (2–12C)optionally including one or more N, O or S with the proviso that any Nincluded in a ring is secondary or is tertiary solely because of analkyl substitution.
 4. The compound of claim 3, wherein X is acyclic. 5.The compound of claim 1, wherein X is aryl, provided that if aryl isphenyl or pyridyl, said aryl must contain at least one substituent andwherein if said aryl is phenyl and contains only one substituent, saidsubstituent must comprise an aryl group or a trialkylsilyl group andwherein said phenyl is not 2,3-dimethylphenyl or fused to an aliphaticring.
 6. The compound of claim 5, wherein X is benzimidazole,benzothiazole, or substituted phenyl.
 7. The compound of claim 1,wherein —CRH-aryl wherein R is H, alkyl, or a heteroaromatic ring,wherein when R is H, aryl is optionally substituted 4-pyridyl, or issubstituted phenyl other than phenyl fused to an aliphatic ring, or issubstituted naphthyl or is substituted 5-membered aryl.
 8. The compoundof claim 7, wherein R is cyclopropyl or a thiophene residue.
 9. Thecompound of claim 1, wherein X is -alkylene-aryl wherein said alkylenecontains at least 2 C, and further optionally contains one heteroatomand/or is substituted by ═O and/or OH provided that if said alkylene isCH₂CH₂, CH₂CH₂CH₂, CH₂CH₂O or CH₂CH₂CH₂O, and said aryl is phenyl, saidphenyl must be substituted; and if said alkylene is CH₂CH₂CH₂Osubstituted by OH, said aryl is other than substituted quinolyl ormonosubstituted phenyl.
 10. The compound of claim 9, wherein saidalkylene comprises a keto substituent.
 11. The compound of claim 9,wherein X is substituted phenyl coupled to (CH₂)_(n) or through a bondto Y to Y(CH₂)_(n), wherein n is 2–5, and Y is NH, O or S.
 12. Thecompound of claim 1, wherein at least one of n1–n3 is
 0. 13. Thecompound of claim 1, wherein n1 is 0 or R¹ is alkyl.
 14. The compound ofclaim 1, wherein both n2 and n3 are
 0. 15. The compound of claim 1,wherein all of n1–n3 are
 0. 16. The compound of claim 1 which is1-{4-[4-(4-Fluoro-benzyl)-phenyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;1-[4-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;1-{4-[3-(4-Amino-2,3,5-trimethyl-phenoxy)-2-hydroxy-propyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;1-(4-Adamantan-1-ylmethyl-piperazin-1-yl)-3,3-diphenyl-propan-1-one;1-(4-Benzothiazol-2-yl-piperazin-1-yl)-3,3-diphenyl-propan-1-one;3,3-Diphenyl-1-{4-[2-(3,4,5-trimethoxy-phenoxy)-ethyl]-piperazin-1-yl}-propan-1-one;1-{4-[2-(3,4-Dimethoxy-phenoxy)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;1-{4-[2-(Benzothiazol-2-ylsulfanyl)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;N-(2,6-Dimethyl-phenyl)-2-[4-(3,3-diphenyl-propionyl)-piperazin-1-yl]-acetamide;2-[4-(3,3-Diphenyl-propionyl)-piperazin-1-yl]-N-methyl-N-phenyl-acetamide;3,3-Diphenyl-1-[4-(1-phenyl-ethyl)-piperazin-1-yl]-propan-1-one;1-[4-(2-Diallylamino-ethyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;1-[4-(2-Dipropylamino-ethyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;1-(4-sec-Butyl-piperazin-1-yl)-3,3-diphenyl-propan-1-one;1-[4-(1-Ethyl-propyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;1-[4-(1-Methyl-piperidin-3-ylmethyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;1-(4-Heptyl-piperazin-1-yl)-3,3-diphenyl-propan-1-one;3,3-Diphenyl-1-(4-pyridin-4-ylmethyl-piperazin-1-yl)-propan-1-one;1-[4-(3,5-Dichloro-phenyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;1-(4-Cycloheptyl-piperazin-1-yl)-3,3-diphenyl-propan-1-one;1-[4-(3,4-Dimethyl-phenyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;1-(4-Biphenyl-4-yl-piperazin-1-yl)-3,3-diphenyl-propan-1-one;1-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;1-[4-(1-Methyl-piperidin-4-ylmethyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;N-{2-[4-(3,3-Diphenyl-propionyl)-piperazin-1-yl]-ethyl}-3,4,5-trimethoxy-benzamide;1-(4-Isopropyl-piperazin-1-yl)-3,3-diphenyl-propan-1-one;1-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;3,3-Diphenyl-1-[4-(4-trimethylsilanyl-phenyl)-piperazin-1-yl]-propan-1-one;3,3-Diphenyl-1-[4-(2-phenylamino-ethyl)-piperazin-1-yl]-propan-1-one;1-{4-[2-(2,4-Difluoro-phenoxy)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;3,3-Diphenyl-1-{4-[2-(2,3,5,6-tetrafluoro-phenoxy)-ethyl]-piperazin-1-yl}-propan-1-one;1-[4-(1-Benzyl-1H-benzoimidazol-2-yl)-piperazin-1-yl]-3,3-diphenyl-propan-1-one;3,3-Diphenyl-1-[4-(phenyl-thiophen-2-yl-methyl)-piperazin-1-yl]-propan-1-one;1-{4-[Cyclopropyl-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;(4-{2-[4-(3,3-Diphenyl-propionyl)-piperazin-1-yl]-ethoxy}-2,3,6-trimethyl-phenyl)-carbamicacid tert-butyl ester;1-{4-[2-(4-Amino-2,3,5-trimethyl-phenoxy)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;1-{4-[2-(4-Methoxy-phenoxy)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;1-{4-[2-(Benzo[1,3]dioxol-5-yloxy)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;1-{4-[2-(2,4-Dichloro-phenoxy)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;1-{4-[2-(4-Fluoro-phenoxy)-ethyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one;or3,3-Diphenyl-1-[4-(2-phenylsulfanyl-ethyl)-piperazin-1-yl]-propan-1-one;or a salt thereof.
 17. A pharmaceutical composition for use in treatingconditions characterized by abnormal calcium channel activity whichcomposition comprises, in admixture with a pharmaceutically acceptableexcipient, a dosage amount of at least one compound of claim
 1. 18. Amethod to treat conditions associated with abnormal calcium channelactivity in a subject which method comprises administering to a subjectin need of such treatment at least one compound of claim 1 or apharmaceutical composition thereof.